Studies of human atherosclerotic plaques and animal models have established a central role for the macrophage in atherogenesis. Further, lesions that tend to rupture, and lead to the majority of clinical manifestations of atherosclerosis, are characteristically rich in macrophages and thus implicate the macrophage as a key regulator of plaque stability. Despite these observations, it is still unclear how the multiple pro- and anti-inflammatory capabilities of the macrophage are balanced within lesions. This interdisciplinary program will use a combination of approaches to probe the role of specific genes in the regulation of the macrophage inflammatory process in atherogenesis. Genes central to monocyte/macrophage trafficking into lesions and pathways regulating their activation and survival within lesions will be the focus of the program. In addition to mechanistic studies in cultured macrophages, all of the projects will specifically test the significance of these target genes in mouse models of atherosclerosis, with an emphasis on the examination of advanced lesions of atherosclerosis that characterize the clinically relevant human disease. Detailed analysis of the mouse lesions will be coordinated and standardized by the Mouse Atherosclerosis Core that will allow direct comparison of the different modulations of the inflammatory response within lesions. By asking whether perturbation of specific inflammatory genes is sufficient to accelerate or retard the progression of advanced lesions of atherosclerosis using identical protocols, this program has the potential to significantly advance our understanding inflammatory processes in atherogenesis and identify targets for intervention with cardiovascular disease progression.